Cyclopentanophenanthrene derivatives and process



Unitfid States Pate it O T 3,064,011 CYCLOPENTANOPHENANTHRENEDERIVATIVES AND PROCESS Lawrence H. Knox, Mexico City, Mexico, assignor,by

mesne assignments, to Syntex Corporation, a corporation of Panama NoDrawing. Filed May 2, 1961, Ser. No. 107,040 6 Claims. (Cl. 260-345.2)

This invention relates to certain new cyclopentanophenanthrenederivatives and to a process for the production thereof.

More particularly, the invention relates to novel 13,17-seco-13,17-oxido-androstane derivatives.

The novel compounds of the present invention are illustrated by thefollowing formula:

In the above formula, R, R and R represent hydrogen or methyl.

More specifically, among the new compounds corresponding to the aboveformula, there are 13,17-semandrostan-3-one 13,17-oxide,2a-methyl-l3,17-secoandr0- stan 3 one 13,17 oxide, 16,9 methyl 13,17secoandrostan 3 one 13,17 oxide, 211,165 dimethyl- 13,17 secoandrostan 3one 13,17 oxide and 2amethyl 13,17 seco 19 nor androstan 3 one-13,17-oxide.

The new compounds illustrated by the above formula exhibitanti-estrogenic activity, anti-androgenic activity, inhibit thesecretion of the pituitary gland and lower the blood cholesterol level,and are usable in a known manner for these purposes.

The process of the present invention may be exemplified by the followinggeneral equation:

chromic acid In the above equation R, R and R have the above explainedmeaning; A represents the carbonyl group the fi-hydroxymethylene group3,064,011 Patented Nov. 13, 1962 or the a-hydroxymethylene group Brepresents the p-hydroxymethylene group or the a-hydroxymethylene groupIn practicing the process above outlined, the 13,17-seco-androstan-13rx-ol-3-one-17-oic acid lactone or its 2amethylderivative and/ or the 16,8-methyl derivative thereof dissolved in borontrifluoride etherate is reacted with lithium aluminum hydride,preferably in suspension in an organic solvent inert to the hydride,such as diethylether, with constant stirring and at low temperature asfor example 0 C. After the period of one half hour to one hour themixture is refluxed for a period of the order of 2 hours. Afterdecomposition of the excess hydride, isolation of the product affords13,17-secoandrostan-3B-ol-13,l7-oxide or the Zen-methyl derivativeand/or the 16fi-rnethyl derivative thereof.

Upon oxidation preferably with an aqueous sulfuric acid solution ofchromic acid, the 13,17-secoandrostan- 3/3-ol-l3,17-oxide or theZea-methyl derivative thereof dissolved in an organic solvent inert tooxidation such as acetone, yields the corresponding 3-ketones i.e.13,17- secoandrostan-3fl-ol-13,17-oxide or the Zen-methyl derivativeand/or the 16,8-methyl derivative thereof.

The following specific examples serve to illustrate but are not intendedto limit the present invention:

Example I A solution of 585 mg. of 13,l7-secoandrostan-3fl-ol-13,17-oxide in 50 cc. of acetone was treated successively with 1.0 g. ofpulverized sodium sulfate and 1 cc. of an 8 N solution of chromic acidin aqueous sulfuric acid at 10 C. After stirring at the same temperaturefor 10 minutes, 1 cc. of propanol and 1 g. of sodium bicarbonate wereadded to decompose the excess oxidizing solution. The reaction mixturewas filtered and the insoluble materials thoroughly extracted withmethylene chloride. Evaporation of the solvent from acetone andmethylene chloride fraction afforded a solid residue which waschromatographed on neutral alumina. The benzene eluates yielded 519 mg.of crude product with a melting point of 13552 C. Severalrecrystallizations from n-heptane gave analytically pure13,17-secoandrostan-3-one-13,17-oxide with a melting point of 156-7 C.,[a] +22.2 (Cl-ICl I Example II 1 g. of2u-methyl-13,l7-secoandrostan-13a-ol-3-one 17-oic acid lactone (F. A.Kincl et al. patent application Serial No. 10,554 filed February 24,1960) was dissolved in 12 cc. of boron trifiuoride etherate, dilutedwith cc. of ether and added with stirring and at 0 C. to a suspensitohnof 1.2 g. of lithium aluminum hydride in 75 cc. of e er.

After 45 minutes at ice-bath temperature, followed by a 2 hour period atreflux, the excess reagent was decomposed by the cautious addition ofethyl acetate andsubsequently water.

The organic layer was separated, dried over anhydrous sodium sulfate andevaporated to dryness under reduced 3 pressure; Recrystallization fromacetone-hexane yielded 2a-methyl-13,17-secoandrostan-3fl-ol-13,17-oxide.

750 mg. of the foregoing compound were oxidized using exactly the sameconditions described in Example I, thus furnishing2u-methyl-13,17-secoandrostan13-one-13, 17-oxide. V

Example -III 1 g. of 16B-methyl-13,17-secoandrostan-l3a-ol-3-one- 17-oicacid lactone (H. J. Ringold et 211., patent application Serial No.38,765, filed June 27, 1960) was reduced following exactly the proceduredescribed in Example II. Recrystallization from acetone-hexane yielded165- methyl-l3,17-secoandrostan-3B-ol-13,17-oxide.

' 750mg. of the above product were treated with 8 N chromic acid suchasdescribed in Example I affording16,8-methyl-13,17-secoandrostan-3-one-13,17-oxide.

Example IV A solution of l 'g. of 20:, 16fi-dimethyl-13,17-secoandrostan-13a-ol-3-one-17-oic acid lactone (H. J. Ringold, US. patentapplication Serial No. 38,765, filed June 27, 1960) in 12 cc. of borontrifluoride etherate was treated following exactly the techniquedescribed in Example 11 thus furnishing2a,16B-dimethyl-13,17-secoandrostan-3B- 01-13, 17-oxide.

Upon oxidation of the foregoing product such as de- I scribed in ExampleI there was obtained 2u,16,B-dimethyl13,17-secoandrostan-3-one-13,17-oxide.

Example V 1 g. of 2a-methyl-13,17-seco-19-nor-androstan-13a-ol-3-one-l7-oic acid lactone (2a-methyl-4,5-dihydroallo-19- wherein R, Rand R are selected from the group consisting of methyl and hydrogen.

2. l3,17-secoandrostan-3-one-13,17-oxide.

3. 2oz methyl 13,17 secoandrostan 3 one 13,17-

oxide. l

4. methyl 13,17 secoandrostan 3 one 13, l7-oxide.

5. 201,165 dimethyl 13,17 secoandrostan 3 one- 13,17-oxide.

6. 2a methyl 13,17 seco 19 nor androstan- 3-one-l3,l7-oxide.

No references cited.

1. A COMPOUND OF THE FOLLOWING FORMULA: